A challenge to medicine since its inception has been the development of methods that permit rapid and accurate detection of diseases. Despite advances in diagnostic technology over the years, the current techniques for the diagnosis of many diseases are either inadequate or cost prohibitive for wide scale application. One such illustrative disease is bladder cancer.
As a worldwide problem, it is estimated that there are 50,900 new cases of bladder cancer per year in Western Europe, 3,700 in Japan and 34,000 in North America (WHO 1984), with at least 3 to 4 times this number of patients attending hospitals for follow-up or treatment.
Bladder cancer occurs in two major forms: superficial and invasive. About 70% of superficial tumors will develop one or several recurrences during a five year follow-up period. The major risk is that the tumor will become invasive. Over 90% of bladder cancers are of the transitional cell type.
The invasive form of bladder cancer accounts for approximately 20%-30% of all bladder cancer. Invasive bladder cancer starts in the mucosa lining the bladder, invades through the basement membrane to reach muscle wall, and finally the pelvic tissues and surrounding organs, including local lymph nodes. The outlook depends on the stage, with five-year survivals from 11%-60%. The treatment is by radiotherapy, chemotherapy and surgery.
Patients with invasive bladder tumors are monitored by cytology and check cystoscopy. Although cytology is a non-invasive and less difficult procedure, it can be prone to error or uncertainty. For example, a positive result by cytology may be helpful, but a negative result cannot be taken as evidence of the absence of a tumor. Further, the reporting varies greatly with the cytologists' experience. Cystoscopy is an invasive, expensive and occasionally hazardous procedure, as it is frequently carried out under anesthesia. Despite the uncertainties associated with cystoscopic checks, they are nevertheless still considered by many medical practitioners as the diagnostic tool of choice because of the absence of better tests.
It is generally agreed that reliable tests for the presence of invasive bladder cancer would be helpful not only for initial detection, but also for recurrence and thus aid in the management of patients with histologically proven bladder cancer. If such a reliable test became available, it might then be used to screen persons at risk, e.g., men over 60 years of age. Further, a test not dependent upon gross visualization of a tumor should allow detection at an earlier stage.
Various tumor markers have been evaluated for their potential as tools in the diagnosis of bladder cancer. Positive serum tests for tumor markers, such as carcinoembryonic antigen (CEA), are usually restricted to advanced tumors. Furthermore, urinary infection has been shown to cause false positives.
In addition to the use of tumor markers, several alternative approaches to diagnosing bladder cancer have been suggested. For example, several urinary enzymes have been described with increased urinary activity in bladder cancer. However, none have been found to be useful in a screening test. Similarly, although antibodies against urothelium and its tumors were at first thought to be tissue-specific, some were later shown to be oncodevelopmental antigens.
Although the inadequacies and problems in the diagnosis of one particular type of cancer are the focus of the preceding discussion, bladder cancer is merely a representative model. The diagnosis of numerous other diseases, including other types of cancer (such as cervical, lung, colorectal, head and neck cancers) as well as non-cancer conditions, have similar problems.
For example, cervical/uterine cancer is the fourth most common form of cancer in women. In 1992 in the U.S. alone, there were approximately 45,000 new cases and 10,000 deaths. The most commonly used procedure for diagnosis is the pap smear which is used to determine the presence of intraepithelial neoplasms and extent of dysplasia on a grading system from I-V, or the presence of invasive cancers. However, the pap test has a high (20%-30%) false negative rate due to poor sampling or reading. In addition, many individuals have Class II pap smears which are atypical and only 20%-25% of this group progress to invasive cancer. Alternatively, colposcopy/cytology can be used. However, this diagnostic approach is uncomfortable to the patient and expensive.
Thus, there is a need in the art for a method of detecting diseases, such as cancers, that is accurate and cost-effective. The present invention fulfills these needs and further provides other related advantages.